This invention relates to new .beta.-carboline-3-carboxylic acid derivatives and to methods of preparing them. The new compounds are useful in psychopharmaceutical preparations being antagonists of benzodiazepines.
EP published patent application No. 30 254, whose disclosure is incorporated by reference herein, discloses compounds represented by the following generic formula: ##STR2## wherein X is oxygen, sulphur or NR.sup.10, wherein R.sup.10 is hydrogen, lower alkyl or cycloalkyl;
R.sup.3 is (a) alkoxy, aryloxy or aralkoxy, each optionally substituted with one or more e.g., 1-3, halogen atoms (F, Cl, Br, I), hydroxy groups, CF.sub.3 groups, or alkoxy groups or with an amino, dialkylamino or alkoxycarbonyl group; or (b) NR.sup.11 R.sup.12, wherein R.sup.11 and R.sup.12 are the same or different and each is (i) hydrogen, (ii) hydroxy, (iii) alkyl, (iv) aryl, (v) aralkyl or (vi) cycloalkyl, the latter four (iii-vi) optionally substituted with a hydroxy, a carboxamido, an alkoxycarbonyl, a carboxy, a monosaccharide or a heterocyclic group, or (vii) amino optionally substituted with alkyl, aryl, aralkyl, or cycloalkyl; or wherein R.sup.11 and R.sup.12 together with the adjoining nitrogen atom form an optionally substituted 5-, 6- or 7-membered heterocyclic ring; with the proviso that R.sup.11 and R.sup.12 cannot both be hydroxy; or wherein X and R.sup.3 together represent a single nitrogen atom; PA1 R.sup.4 is hydrogen, alkyl, cycloalkyl, aralkyl, phenyl, or an alkoxyphenyl group containing up to 10 carbon atoms, PA1 R.sup.A is F, Cl, Br, I, NO.sub.2, NR.sup.13 R.sup.14, NHCOR.sup.13, CN, COOR.sup.13, OR.sup.13, SCH.sub.3 or SO.sub.2 NR.sup.11 R.sup.12 ; wherein R.sup.13 and R.sup.14 each is hydrogen or alkyl containing up to 6 carbon atoms and optionally substituted with hydroxy or halogen (F, Cl, Br, I) and wherein R.sup.11 and R.sup.12 are as defined above PA1 and wherein there may be 1-4 identical or different R.sup.A s; and PA1 R.sup.9 is hydrogen, alkyl or alkoxycarbonyl each of the latter two containing up to 8 carbon atoms; PA1 with the provisos: PA1 that R.sup.11 and R.sup.12 cannot both be hydrogen, when X is oxygen and R.sup.4, R.sup.A and R.sup.9 each is hydrogen, PA1 that one of the substituents R.sup.11 and R.sup.12 cannot be hydrogen when the other is amino and when X is oxygen and R.sup.4, R.sup.A and R.sup.9 each is hydrogen, and PA1 that R.sup.4, R.sup.A and R.sup.9 each cannot be hydrogen when X is oxygen and R.sup.3 is OCH.sub.3. PA1 anxiety and tension conditions, with and without depressions, unrest, and disturbances resulting from stress situations or excess of stimulations, as well as pathological aggressiveness. PA1 R.sup.2 is hydrogen, methyl, ethyl, n-propyl or iso-propyl, provided that R.sup.1 is not methyl, when R.sup.2 is hydrogen. PA1 R.sup.3 is hydrogen, methyl, ethyl, n-propyl or iso-propyl, provided that R.sup.3 is not methyl, when R.sup.2 is hydrogen, with glyoxylic acid or formaldehyde and thereupon dehydrogenating the intermediarily obtained 1,2,3,4-tetrahydrocarboline derivative and if R.sup.3 is hydrogen followed by etherification of the hydroxyl group by reaction with a compound of the general formula R.sup.1 X, wherein R.sup.1 is methyl, ethyl, n-propyl or iso-propyl and X represents a halogen atom.
The class of compounds represented by the above formula are described as being able to displace flunitrazepam from benzodiazepine receptors, and in contrast to benzodiacepine, chlordiacepoxide and diazepam to inhibit aggression without causing impaired motor coordination, which means that the compounds represented by the above formula are suitable for use as non sedating anticonvulsants, antiaggressives and anxiolytics or for stress protection. As such, they can be used for treatment of the following indications: